Project summary: Alcoholic liver disease is characterized by lipid accumulation within the liver that may progress to fibrosis and cirrhosis. Hypoxia has been postulated to play a role in alcohol-mediated liver injury. Hypoxia-inducible factors [HIFs] are transcriptional factors that mediate cellular responses to hypoxia. A recently described transgenic mouse model of liver-specific HIF activation demonstrates lipid accumulation and hepatomegaly, lending more credence to earlier observations that hypoxia may have a mechanistic relationship to alcoholic liver disease. The observations that HIF activation depends to a large degree upon the recruitment of CBP/P300 proteins (transcriptional co-activators with histone acetyltransferase activity) and that HIFs themselves co-immunoprecipitate with histone deacetylases confirm that epigenetic phenomena play a large role in the HIF-mediated response. Evidence also suggests that histone acetylation is modified by acute ethanol exposure, although the epigenetic effects of chronic ethanol consumption are unknown. This project has two broad goals related to the pathogenesis of chronic ethanol mediated liver injury: first to determine the importance of HIF-pathway activation, and second, to investigate epigenetic events as potential pathogenic mechanisms of chronic alcohol consumption, particularly as they relate to the activation of HIF pathway target genes. Utilizing a combination of approaches, including transgenic mouse models previously unutilized in alcohol research and existing pharmacological agents, the importance of HIF pathways and epigenetic events in liver disease will be explored. Relevance: Liver injury is one of the most common morbidities associated with consumption of alcohol, and is associated with significant mortality. This study proposes to incorporate models derived from cancer biology with the goal of elucidating fundamental disease causing changes in the liver associated with chronic alcohol consumption. The outcomes of this work will provide crucial information towards our understanding of liver disease caused by alcohol that will have implications for the development of therapeutic strategies in this area.